This research was initiated and carried out by Dr. B. Vithal Shetty, a guest researcher from the FDA who is co-principal investigator of this project. A novel approach to the design of new antimicrobial agents has been developed. The overall purpose of the program is the rational design and synthesis of compounds that have combined anti-bacterial, anti-viral and anti-fungal activity. Specifically targeted in the rational design are enveloped viruses such as herpes viruses and HIV. The new compounds have novel structural features which include a dimeric attachment of a known hydrophobic antimetabolite (for example, aminoadamantane analogues) through a very hydrophilic bridge. The hydrophilic portion of the molecule has a high affinity for glycoprotein components of the microbial cell wall. This affinity will deliver the toxic moieties to the cell surface, providing a mechanism for efficient activity. The potential exists for inhibition of replication of such viruses as HIV and, through the attachment of the toxic molecule to the viral coat, a mechanism for killing the virus. Using this strategy, several compounds were examined and certain of these possessed impressive antimicrobial potency. One potent bis-adamantamine analogue (B.V. Shetty, U. S. Patent No. 5,221,693) has been licensed through the NIH technology transfer program for development as a broad spectrum antimicrobial drug, especially for the treatment of gingival infections. This bifunctional approach to antimicrobial drug design has now been extended to include incorporation of 4-quinolone moieties into the structures. The choice of 4-quinolones stems from their selective effects on prokaryotic DNA replication caused by inhibition of the action of topoisomerase II. Eukaryotic DNA replication is much less susceptible to the action of quionolone antibacterials. Although these antibacterials are reported to have little or no anitviral activity, it seems likely that this is due to poor penetration of the viral envelope. By rational attachment of lipohilic bridges, a strategy has been developed to deliver the 4-quinolone moiety across the viral coat. Lead compounds have been tested and found to have potent anti-HIV, as well as antibacterial acitivity. Work is now in progress to optimize these lead compounds.